The Critical Role of Genetics and Genomics in the Future of Healthcare

In talking with Dr. Robert Green, one of the handful of leading-edge researchers and thinkers on the promise of genomics in transforming health and healthcare, I have gained some quite interesting insights.

Dr. Green is a physician-scientist at Brigham and Women’s Hospital and the Harvard Medical School and has focused much of his professional life on a subject of great passion to me, patient empowerment. As strange as it may sound, he has had to do a considerable amount of clinical study work to prove to the medical community that the consequences of doctors telling patients that they are at serious risk of a degenerative and currently incurable disease are, on balance, positive. His work in that regard has been done through a series of studies called the REVEAL Study, for which he has been the principal investigator.

Genomics, according to the Wikipedia definition, is “a discipline in genetics concerned with the study of the genomes of organisms. The field includes efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping.”

When I studied genetics in high school as part of a biology course, all I remember is that brown eyes are dominant and blue eyes are recessive, and that, therefore, the chances of someone being born with blue eyes is 1 in 4. I also learned that certain conditions, like Down Syndrome, resulted from individuals having a third copy of Chromosome 21, with the result that such an individual would experience intellectual disability. Later in the 1960’s, after watching the film Alice’s Restaurant, which starred Arlo Guthrie, the son of the famous folk singer, Woody Guthrie, I learned that Woody Guthrie died from a horrible neurological disease called Huntington’s disease. Wikipedia defines Huntington’s disease as follows:

“Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington’s chorea.”

As the Wikipedia article goes on to point out,

“The disease is caused by an autosomal dominant mutation in either of an individual’s two copies of a gene called Huntington, which means any child of an affected person typically has a 50% chance of inheriting the disease.”

The way we learned, and have talked about, genetics over the last several decades, has caused us to have a few deep misconceptions about how it works relative to health and the effect genes have on the likelihood of someone having a future medical condition. There are two major conceptual flaws in how people outside the field of genomics think about genomics and the study of genetics:

Genetic influences on most diseases are much more complex in most cases than we would think would be the case, based on genetically driven conditions like Down Syndrome or Huntington’s disease.

A small portion of any population with a particular disease will have a genetic profile that matches with, and predicts the future prevalence of a disease. For example, relative to Alzheimer’s disease, about 5% – 10% of all Alzheimer’s disease cases occur earlier in adult life, often as early as when an individual is in his or her 30’s or 40’s. These cases, according to the medical research literature, occur because of the presence of specific genes. As the Wikipedia entry states:

“Familial Alzheimer disease is caused by a mutation in one of at least 3 genes: presenilin 1, presenilin 2 and amyloid precursor protein (APP).[4][5][6]”

However, the other 90-95% of Alzheimer’s disease cases probably result from various combinations of genes, which interact with behavioral and environmental factors that we do not yet understand. Dr. Green is doing cutting-edge research on an innovative way of thinking about Alzheimer’s disease, by comparing cases in which individuals deteriorate, because of Alzheimer’s disease, over relatively short time periods (a few years) and those in which others deteriorate over much longer periods (as much as 20 years.) He is trying to isolate genes that are present in the short-cycle deterioration cases, compared with the longer-cycle cases. He is starting to make great progress, but the research is costly and the funding is more limited than it was a few years ago.

The key lesson from his work and the work of other colleagues who do cancer research or research into other diseases is that most medical conditions result from complex interactions of multiple genes, not the single-gene drivers that were believed to be the major causes of disease decades ago when this field was much newer.

There are two separate issues with genes under particular study today: the genetic sequence and epigenetics. Changes in the sequence determine whether someone has a pathogenic variation or mutation in a particular gene, causing a failure of that gene to function. Changes in the expression of that gene, also known as “epigenetics” determines whether gene functions are turned up or down in intensity. Because most diseases are caused by multiple genes having the disease-associated variation in the sequence of a gene does not necessarily mean that and individual will get the disease.

The discipline of epigenetics has demonstrated that, although the regulation of genes makes a difference to our health, there are additional epigenetic factors that cause a gene to be “expressed,” which loosely means that it has been “turned on.” Genetic effects can be turned up or down in function. Thus, there are many situations in which two people with the same gene will have different effects, based on the gene being expressed differently in one person than in the other.

Implications of this research

Why is it important to get our thinking our thinking right on these points?

• Scientific research to identify genetic influences on the presence, absence, or seriousness of diseases has been redirected away from simpler single causes – single effect relationships between genes and medical consequences, as should be the case. As we evaluate the kind of research that is needed, we need to adjust our expectations as to what approach the research should take.
• The fact that genetic expression is often influenced by behavioral and environmental factors should remind us that our behaviors have more effect on what genes get expressed and how they are expressed to drive our health status than we would like to admit. We are more in control of our fate with respect to many medical conditions, although there still are sizable numbers of people afflicted with medical conditions driven by single genes.
• Cells inside our body can have genetic profiles different from the genetic profiling of other cells. That is why tumors that are removed from a human body through a biopsy can undergo a genetic analysis that provides significant insight as to their future likelihood of being malignant and what kind of treatment might work best.
• Our long term success in unlocking the mystery of why some people get horrible diseases like Alzheimer’s and others do not will depend both on more individualized gene sequencing at an increasingly lower cost and on linking genetic conditions to other information we know about an individual. Steve Jobs had a genetic analysis of his tumor done about six years ago, and it cost over $100,000. We will see a full genetic profile being done on any of us within a few years that will cost less than $1,000. Moreover, that price will keep going down.
• Genetic profiling will not only be useful in determining our susceptibility to particular diseases, but it will help determine what medications and dosages are optimal for us. Today, there are online dosage calculators at sites like www.rxdesktop.com/dosagecalculator.html that, while imperfect, give us some insights as to the areas in which dosage adjustments might be considered because of different physical profiles. In the future, we can expect similar adjustments based upon genetic profiles.
• The genetics revolution also reminds us of the importance of giving every person an individually controlled, comprehensive, livelong, portable and secure personal health record. I have devoted the last several years of my life trying to move the country forward in this regard with my leadership of the Dossia Service Corporation. Sadly, there is a great deal of institutional resistance on the part of many members of the medical community, as well as the health insurance community, to having control of a comprehensive health record in the hands of the individual or his or her caregiver.
• Electronic medical records should also contain genetic information, if the patient consents to disclosing that information to the physician. The difference between a personal health record controlled by a patient and an electronic medical record controlled by the physician is that the personal health record will contain the records of all physicians, as well as other personal health information. Ultimately, personal health information, like that contained in a genetic profile, belongs to the patient.

We are in the midst of a time when great discoveries that will unlock the mysteries of many diseases are not far away from happening. Research needs to be done, and that research requires money. If you are interested in learning more, or even contributing to this effort, please check out Dr. Green’s web site at www.genomes2people.org and contribute to his effort at giving.brighamandwomens.org/G2P.